Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. The increased workload on the heart and a progressive decrease in its pumping ability, cause an increase in cardiomyocyte size, enhanced protein synthesis, and a higher organization of the sarcomere. Initially, the increased workload that results from high blood pressure or loss of contractile tissue induces compensatory cardiomyocyte hypertrophy and thickening of the left ventricular wall, thereby enhancing contractility and maintaining cardiac function. However, over time, the left ventricular chamber dilates, systolic pump function deteriorates, cardiomyocytes undergo apoptotic cell death, and myocardial function progressively deteriorates.
While physiological cardiac hypertrophy may represent a positive adaptive response to increased workload, pathological hypertrophy is a principal risk factor for the development of congestive heart failure and subsequent cardiac death. In fact, congestive heart failure is a leading cause of death in industrialized nations.
It is recognized that in most instances hypertrophy is not a compensatory response to the change in mechanical load, but rather is a maladaptive process. Accordingly, modulation of myocardial growth without adversely affecting contractile function is increasingly recognized as a potentially auspicious approach in the prevention and treatment of heart failure.
Factors that underlie congestive heart failure include high blood pressure, ischemic heart disease, exposure to cardiotoxic compounds such as anthracycline antibiotics, and genetic defects known to increase the risk of heart failure.
The stimuli inducing cardiac hypertrophy include various growth factors, hormones, and cytokines such as endothelin-1, angiotensin II, insulin-like growth factor-1, myotrophin, and cardiotrophin-1. Mechanical stress is another important stimulus for cardiac hypertrophy. Mechanical stress is considered to be the trigger inducing a growth response in the overloaded myocardium. Furthermore, mechanical stress induces the release of growth-promoting factors, such as angiotensin II, endothelin-1, and transforming growth factor-β, which provide a second line of growth induction.
By using an in vitro neonatal cardiomyocyte culture system, it has been demonstrated that mechanical stretch induces signal transduction characterized by simultaneous activation of multiple second messenger pathways, such as phospholipases (C, D, and A2), protein kinase C (PKC), the JAK/STAT pathway, mitogen-activated protein (MAP) kinase cascades, and calcium/calmodulin-dependent protein phosphatase calcineurin pathway. Molecules in these pathways may be targets for therapies designed to prevent the progression of cardiac hypertrophy.
Signaling pathways related to cardiac hypertrophy have been reviewed in Frey and Olson, 2003, Cardiac hypertrophy: the good, the bad, and the ugly. Annu. Rev. Physiol. 65:45-79, which is incorporated herein by reference in its entirety.
Vitamin A (retinol) and its natural and synthetic derivatives (retinoids) participate in a wide range of biological processes, including vision, neoplasia, embryonic development, normal reproductive function, regulation of epithelial and hematopoietic cellular differentiation, and cardiovascular development. Retinoic acid (RA), the active metabolite of vitamin A, is the main signaling retinoid in the body. RA functions by binding to nuclear receptor proteins.